Cock gait in manganese intoxication.
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Adult↗
Biomedical subjects
D B Calne
Publications and source records attributed to D B Calne.
Contributions of positron emission tomography to elucidating the pathogenesis of idiopathic parkinsonism and dopa responsive dystonia.
The metabolic mapping of brain activity, using PET, confirms the conventional wisdom of neurophysiology. In studies of pathophysiology, PET has yielded evidence that has generated new hypotheses. Progression of the lesion detectable with fluorodopa, in human subjects exposed to MPTP, raises the possibility of a transient environmental event being a cause of progressive neurodegeneration. Studies with fluorodopa in Idiopathic Parkinsonism indicate that the rate of loss of neurons is faster initially, and then tends to approach the normal age-related decline. In dopa responsive dystonia, the finding of normal fluorodopa PET led to the prediction that the lesion would be functional rather than anatomical; this has been confirmed by the identification of a defect in dopamine synthesis in this disorder. Filally, new PET ligands show promise for future studies designed to unravel the pathogenesis of diseases involving the basal ganglia.
Brain↗
"Familial Parkinson's disease"--a case-control study of families.
BACKGROUND: Parkinson's disease (PD) patients frequently report a family history of PD and this may provide etiological clues to PD. It has also been suggested that a report of a negative family history is reliable. We studied the prevalence of PD in relatives of PD patients to assess the reliability of family history and to evaluate possible explanations of "familial PD" (fPD). METHODS: 81 of 650 (12.5%) PD probands (all PD patients seen at clinic in 4 years) reported a positive family history of PD. Each fPD proband was matched with non-familial PD (nfPD) proband by gender and year of birth. Screening and follow-up questionnaires were mailed to relatives to obtain information concerning pedigree and presence of neurodegenerative disease. Available family members (regardless of disease status) were examined. RESULTS: On examination, 8 persons, said to be "normal" by probands, relatives and themselves, had definite or possible PD (5 fPD, 3 nfPD). The prevalence rate of PD among first and second degree living relatives of probands varied significantly between fPD and nfPD groups (6269/100,000 versus 1190/100,000; p < 0.001). The weighted prevalence (taking into account the proportions of fPD and nfPD within the clinic) was 1822/100,000, a value more than 5 times higher than reported prevalence rates of PD in the general population (p < 0.001). The prevalence rate was greater in first degree relatives than second degree. CONCLUSIONS: "Familial parkinsonism" cannot be explained merely by size of or advanced age within families. Significant numbers of previously unrecognized PD patients may be identified despite a "negative" family history. That is, the patient's report of an absence of familial parkinsonism is frequently inaccurate. The prevalence rate in relatives of PD patients appears to be higher than the general population-regardless of the family history reported by a PD patient. We believe our study suggests that genetic influences or early life environmental exposures are likely to be of etiological importance in PD.
Adult↗
Efficacy, stability and predictors of outcome of pallidotomy for Parkinson's disease. Six-month follow-up with additional 1-year observations.
We tested the efficacy, stability and predictors of outcome of unilateral pallidotomy used to treat patients with Parkinson's disease inadequately controlled with pharmacotherapy (IP). The surgical procedure was as simple as possible; we used CT rather than MRI, and we omitted microelectrode recording. We studied 24 patients with IP; 22 of these patients had drug-induced dyskinesias. There was a significant and stable improvement in all the major parkinsonian motor signs in the OFF (medication) state on the contralateral side. In the ON (medication) state peak-dose dyskinesias were alleviated on the contralateral side. The only significant and stable change on the ipsilateral side was improvement in dyskinesias less marked than on the contralateral side. The improvement in Unified Parkinson's Disease Rating Scale motor scores in the OFF state increased with age. The improvement in total dyskinesia scores occurred irrespective of age, but increased with duration of disease, duration of dyskinesias and baseline severity of dyskinesias. Five patients had transient neurological complications while facial paresis was permanent in one subject. Our results are similar to those obtained by others who used the time consuming microelectrode recording technique for localization. By simplifying the procedure in the way that we describe, the operation could become available to a greater number of patients.
Adult↗
Presynaptic and postsynaptic striatal dopaminergic function in patients with manganese intoxication: a positron emission tomography study.
We performed PET on four patients with chronic industrial Mn intoxication; presynaptic and postsynaptic dopaminergic function were measured with [18F]6-fluoro-L-dopa (6FD) and [11C]raclopride (RAC). All patients had a rigid-akinetic syndrome; they had no sustained benefit from L-dopa. Influx constants (Ki) of 6FD were normal in the caudate and putamen. RAC binding was mildly reduced in the caudate and normal in the putamen. We conclude that nigrostriatal dopaminergic dysfunction is not responsible for the parkinsonism caused by chronic Mn intoxication. The pathology is likely to be downstream of the dopaminergic projection.
Adult↗
Lamotrigine trial in idiopathic parkinsonism: a double-blind, placebo-controlled, crossover study.
Increased glutamatergic transmission in the basal ganglia is implicated in the pathophysiology of idiopathic parkinsonism (IP). We investigated the effects of lamotrigine (LTG), a glutamate-release inhibitor, in the symptomatic treatment of IP in two double-blind, placebo-controlled studies. Single doses of L-dopa/carbidopa (equal to 50% of the usual morning dose) were administered together with either LTG (100, 200, or 400 mg) or two random placebo doses in 14 patients with IP. The patients were assessed using the Modified Columbia Rating Scale (MCRS) and the Purdue Pegboard Test (PPBT) at multiple intervals over 8 hours. There were no significant differences between the placebo doses and the three doses of LTG on the MCRS and PPBT scores. In a 3-month study, 12 patients took LTG titrated up to 400 mg or placebo with their antiparkinsonian medication for 3 months and were then crossed over. Nine of 12 patients did not complete the study because of dyskinesia (n = 2), hallucinations (n = 3), and deterioration of parkinsonian symptoms (n = 4) on LTG. There was no significant difference between placebo and LTG on the MCRS and PPBT in the three patients who completed the study. The results failed to demonstrate any symptomatically beneficial effects of LTG in IP.
Adult↗
Fluorodopa and raclopride PET analysis of patients with Machado-Joseph disease.
We performed [18F]6-fluoro-L-dopa (6-FD) and [11C]raclopride (RAC) PET studies in six patients with Machado-Joseph disease (MJD) (age, 17 to 61 years; duration of illness, 3 to 10 years), normal controls (n = 10 in 6-FD-PET, n = 8 in RAC-PET), and patients with idiopathic parkinsonism (n = 15 in 6-FD-PET). The youngest patient with MJD had prominent dystonia and pyramidal features (type 1 MJD), whereas the remainder were prominently ataxic (types 2 and 3 MJD). Striatal RAC binding was normal in patients with MJD. Striatal 6-FD influx constants (Ki) were low in the range of idiopathic parkinsonism in two patients with MJD (youngest and oldest patients), whereas striatal Ki were normal in the remaining patients with MJD. The impairment of the nigrostriatal dopaminergic pathway did not correlate with the phenotype, CAG repeat length, disease duration, or age of onset of patients with MJD. Our results suggest that striatal D2 receptors are normal and the nigral damage is diverse in MJD.
Adolescent↗
Manganese intoxication in the rhesus monkey: a clinical, imaging, pathologic, and biochemical study.
We gave three adult rhesus monkeys seven IV injections of manganese chloride at approximately 1-week intervals. We evaluated neurologic status by serial clinical examinations and performed a levodopa test if the animal developed features of basal ganglia dysfunction. After the animals were killed, we performed neuropathologic, neurochemical, and laser microprobe mass analysis (LAMMA) studies. Two of three animals developed a parkinsonian syndrome characterized by bradykinesia, rigidity, and facial grimacing suggestive of dystonia but not tremor. Neither animal responded to levodopa. Autopsy demonstrated gliosis primarily confined to the globus pallidus (GP) and the substantia nigra pars reticularis (SNr). We detected focal mineral deposits throughout the GP and SNr, particularly in a perivascular distribution. LAMMA studies noted that mineral deposits were primarily comprised of iron and aluminum. The severity of pathologic change correlated with the degree of clinical dysfunction. These studies demonstrate that, in contrast to Parkinson's disease (PD) and MPTP-induced parkinsonism, manganese primarily damages the GP and SNr and relatively spares the nigrostriatal dopaminergic system. Further, the results suggest that Mn-induced parkinsonism can be differentiated from PD and MPTP-induced parkinsonism by the clinical syndrome and response to levodopa. The accumulation of iron and aluminum suggests that iron/aluminum-induced oxidant stress may contribute to the damage associated with Mn toxicity.
Animals↗
Presynaptic nigrostriatal function in genetically tested asymptomatic relatives from the pallido-ponto-nigral degeneration family.
Pallido-ponto-nigral degeneration (PPND) is a dominantly inherited disorder with parkinsonism. We performed PET with [18F]fluorodopa (FD) and, later, gene testing in 12 asymptomatic relatives at risk from a family with PPND and compared the striatal FD uptake constant (Ki) in them with 4 symptomatic individuals and 10 normal control subjects. Four relatives with positive linkage had a significantly reduced Ki from the normal control subjects but to a lesser degree than the symptomatic patients. The mean Ki in the relatives with negative linkage (n = 8) did not differ from normal control subjects. In conclusion, we identified reduced dopaminergic function in asymptomatic relatives with positive genetic linkage from the PPND family. Most of the reduction in this disorder occurs in the fifth decade, when the disease manifests clinically.
Adult↗
Selegiline in Parkinson's disease.
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Antiparkinson Agents↗
Diagnosis and treatment of Parkinson's disease.
At its inception, the disease may be among the hardest neurologic disorders to recognize. Other problems may arise later, both from the disease and from its treatment. Indeed, adverse drug effects range from orthostatic hypotension to drug-induced dyskinesias and psychiatric disorders. For many such difficulties, clinical experience can offer practical suggestions.
Aged↗
Screening Parkinson's disease: a validated questionnaire of high specificity and sensitivity.
A questionnaire designed to screen Parkinson's disease (PD) in literate populations has been developed. It consists of nine questions, self-administered at medical facilities or by mail, and a scale of weights for ascribing scores to specific questions when the answer is positive. The questions were chosen to be symptom specific for PD and the weights were determined from answers provided by 37 PD patients in a neurological outpatient clinic. The questionnaire sensitivity was tested on a different PD population from the same outpatient clinic--50 individuals--and the specificity on a group of 100 ophthalmological patients. The sensitivity was 100% and the specificity was 100%. Three individuals who screened positive among the 100 ophthalmological patients were assessed and given a new diagnosis of PD. This questionnaire therefore constitutes an instrument that should prove valuable as the first stage of a door-to-door survey. It has high sensitivity and specificity.
Adult↗
The use of PET in Parkinson's disease.
Activation studies with positron emission tomography (PET) have provided an understanding of the pathophysiology of akinesia and tremor in Parkinson's disease (PD). [18F]6-fluoro-L-dopa (FD)-PET and dopamine receptor imaging by PET can assist in the differential diagnosis of various forms of parkinsonism. FED-PET is capable of detecting subclinical dopaminergic deficits. This allows not only the early or preclinical detection of PD but also the investigation of subclinical lesions of the substantia nigra in PD-related disorders. Longitudinal studies of PD and MPTP induced parkinsonism have provided new insight into the pathogenesis of PD.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Patterns of asymmetry do not change over the course of idiopathic parkinsonism: implications for pathogenesis.
We investigated the asymmetry of focal deficits of bradykinesia in a cross-sectional study of 198 patients with idiopathic parkinsonism. We have analyzed the difference in Unified Parkinson's Disease Rating Scale (UPDRS) scores between the more and less affected sides in these patients, whose duration of symptoms ranged from 1 to 15 years. There was no significant change in the asymmetry or focality over this period; the deficit for each side progressed faster initially and then approached the normal age-related linear rate of decline. Previous studies indicate that there is an inverse linear relation between the UPDRS bradykinesia score and the nigral dopaminergic cell count. We infer that the rate of death of nigral dopaminergic neurons is predetermined from the time of onset of pathogenesis. The simplest explanation is that a causal event kills some cells and damages others so that they undergo premature death. This sequence of changes could be implemented through environmental (toxic or viral) damage to the genome. Several diverse sources of evidence support this concept.
Adult↗
Western Nebraska family (family D) with autosomal dominant parkinsonism.
The etiology of Parkinson's disease (PD) remains uncertain. Environmental influences may have an important role, but genetic factors have been firmly implicated in several recently reported kindreds. We studied a family (family D) whose ancestors probably immigrated to the United States from England. The pedigree contains 188 individuals spanning six generations with 18 affected members. Autosomal dominant inheritance is present. Typical levodopa-responsive PD with bradykinesia, rigidity, resting tremor, and impaired postural reflexes develops. Eye movement abnormalities, pyramidal and cerebellar signs, sensory disturbances, and orthostatic blood pressure changes do not occur. Disease progression is slow. PET with [18F]-6-fluoro-L-dopa (FD) performed on an affected individual revealed decreased uptake of FD in a pattern consistent with PD. Autopsy performed on another affected individual demonstrated neuronal and pigmentary loss, gliosis, and Lewy bodies in the substantia nigra pars compacta. This large kindred appears to represent a neurodegenerative disorder closely resembling, if not identical to, idiopathic PD.
Aged↗
MRI and PET studies of manganese-intoxicated monkeys.
Using MRI and PET, we investigated the consequences of manganese intoxication in a primate model of parkinsonism and dystonia. Three rhesus monkeys were injected intravenously with doses of 10 to 14 mg/kg of MnCl2 on seven occasions, each a week apart. Two animals became hypoactive with abnormal extended posturing in the hind limbs. These motor disturbances did not improve with administration of levodopa. In all three monkeys, T1-weighted MRI demonstrated high signal intensities in the regions of the striatum, globus pallidus, and substantia nigra. No significant changes were found on [18F]6-fluoro-L-dopa, [11C]raclopride, or [18F]fluorodeoxyglucose PET. These results are consistent with the pathologic findings, which were primarily confined to the globus pallidus, and indicate that manganese intoxication is associated with preservation of the nigrostriatal dopaminergic pathway, despite clinical evidence of parkinsonian deficits. Chronic manganese intoxication may cause parkinsonism by damaging output pathways downstream to the nigrostriatal dopaminergic pathway. This is consistent with the demonstrated lack of therapeutic response to levodopa.
Animals↗
Biochemical and fluorodopa positron emission tomographic findings in an asymptomatic carrier of the gene for dopa-responsive dystonia.
We report cerebrospinal fluid monoamine metabolite analyses and 6-[18F]fluoro-1-dopa positron emission tomography (FD-PET) from an asymptomatic carrier of the gene for dopa-responsive dystonia. Cerebrospinal fluid homovanillic acid, tetrahydrobiopterin, and neopterin concentrations were reduced in this man and in his affected children. His FD-PET was normal, as we have previously found in dopa-responsive dystonia. Neurological function and FD-PET may be normal despite marked abnormality in dopamine metabolism.
Adolescent↗
Dopa-responsive dystonia.
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Dihydroxyphenylalanine↗